Preparation of (5-benzyloxy-3-indole)-alkylamines



United States Patent PREPARATION OF (S-BENZYLOXY-Zi-INDOLE} ALKYLAMINESMerrill E. Specter, Kalamazoo Township, Kalamazoo County, Mich.,assignor to The Upjohn Company, Kalamazoo, Mich., a corporation ofMichigan No Drawing. Application May 24, 1952, Serial No. 289,871

11 Claims. (Cl. 260-319) The present invention relates to novel organiccompounds, and is more particularly concerned with a novel process forthe preparation of (-benzyloxy-3-indole)- alkylamines, and with theproducts thus-produced. This application is a continuation-in-part of myprior filed copending application Serial Number 282,273 filed April 14,1952.

The compounds of the present invention may be represented by theformula:

11 alkyl XOHO CHzCHaN-CH 1' alkyl wherein X represents phenyl,halophenyl, lower alkoxyphenyl, or lower alkylphenyl, Y representshydrogen, phenyl, halophenyl, lower alkoxyphenyl, or lower alkylphenyl,and R represents hydrogen or lower alkyl.

It is an object of the present invention to prepare novel compounds,(5-benzyloxy-3-indole)-alkylamines, and acid addition salts thereof. Itis a further object of the present invention to provide a novel processfor the preparation of the (5-benzyloxy-3-indole)-alkylamines and acidaddition salts thereof. Other objects of the present invention will beapparent to one skilled in the art to which the invention pertains. Thenovel compounds of the present invention are important intermediates inthe preparation of serotonin analogs. Serotonin, S-hydroxy-3-(2-aminoethyl)-indole creatinine sulfate, [Rapport, J. Biol. Chem.180, 961, (1949)], has been shown to possess powerful vasoconstrictorqualities. The compounds of the present invention, the(5-benzyloxy-3-indole)- alkylamines are debenzylated when subjected tohydrogenolysis in the presence of a catalyst, such as palladiumcharcoal,for example, to yield the serotonin analogs and the thus-producedserotonin analogs have also demonstrated marked vasoconstrictorqualities.

The process of the present invention involves the reductive alkylationof the amino radical of 5-benzyloxy-3- (2-aminoethyl)-indoles, morebriefly named, S-benzyloxytryptamines, represented by the formula:

wherein X, Y, and R have the values specified above. Representative5-benzyloxy-3-(2-aminoethyl)-indoles include the following:5-henzhydryloxy-3-(2-aminoethyl)- indole,2-methyl-5-benzyloxy-3-(Z-aminoethyl)-indole, 5- (para,para'dimethylbenzhydryloxy)-3-(2-aminoethyl)- indole, 5(para,para'-dimethoxybenzhydryloxy) 3 (2- aminoethyD-indole, 5(para,para'-dichlorobenzhydryloxy)-3-(2-aminoethyl)-indole, and thelike. The 5- 2,789,984 Patented Apr. 23, 1957 wherein X, Y, and R havethe values specified above, with chloroacet-onitrile, more fullydisclosed in U. S. Patent 2,728,778. The S-benzyloxyindoles are preparedby the reductive eycliza-tion of 5-benzyloxy-;i,2-clinitrostyrenes, asmore fully disclosed in my prior filed copending application SerialNumber 273,149, filed February 23, 1952, and the5-benzyloxy-,B,2-dinitrostyrenes are prepared by the dehydration of5-benzyloxy-2-nitro-u-l1-(1- nitroalkyD] benzyl alcohols, as more fullydisclosed in my prior filed copending application Serial Number 273,148,filed February 23, 1952. The 5-benzyloxy-2-nitro-a-[1- (l-nitroalkyD]benzyl alcohols are prepared by con-densation of5-benzyloxy-2-nitrobenzaldehydes [Burton, J. Chem. Soc. 1935, 1265 orPortmann et al., Helv. Chim. Acta. 31, 1381 (1948)], with al-nit-roalkane, as more .fully disclosed in U. S. Patent 2,698,345.

in the method of the present invention the starting free base,5-benzy-loxy-3-(Zaam-inoethyI)-indole, dissolved in a suitable solventsuch asmethan-ol, ethanol, isopropanol, or the like, is added to aplatinum catalyst whereafter a dia-lkyl ketone, such .as acetone,di-ethyl ketone, methyl ethyl ketone, methyl-n-propyl ketone, ethylpropyl ketone, dipropyl ketone, or the like is added, and the mixture isthereupon subjected to reductive alkylation in an atmosphere ofhydrogen. The hydrogen pressure employed for the reductive alkylationmay range from slightly under atmospheric to about two or threeatmospheres, although higher pressures can also be used. The reaction isusually carried out at a temperature of about 25 degrees centigrade, butalso can be conducted satisfactorily in a temperature range betweenabout zero degree centigrade and the boiling point of the solventemployed, for example, between about zero and degrees centigrade. Thereact-ion is usually complete in a period of a few minutes to severalhours, with a shorter reaction time, of course, being required at thehigher temperatures and greater hydrogen pressures. The desired freebase, the (5-benzyloxy-3-ind-ole)aalkylamine, is thereupon obtained,usually as a heavy oil, by filtering to remove the catalyst, anddistilling the solvent utilized. The free base is usually converted to amore adaptable crystalline salt such as the hydrochloride, hydrobromide,sulfate, acetate, tartrate, picrate, citrate, or the like, by reactingthe free base with a stoichiometric quantity of the corresponding acid.The resulting (5-benzyl-oxy-3-indoley alkylarnine acid addition saltsmay be further purified, if so desired, by recrystallizing from analcohol such as methanol, ethanol, isopropano-l, or the like, withisopropanol being preferred. If a 5-benzyloxy-3-(2-aminoethyD-indoleacid addition salt, such as the hydrochloride, sulfate, hydrobromide,picrate, or the like is utilized as the star-ting compound, the freebase is initially isolated by reacting theS-benzylcxy-3-(2-aminoethyl)-indole acid addition salt, dissolved inwater, with an excess of alkali, such as sodium hydroxide, calciumhydroxide, or the like, to liberate the free base. Upon extracting withan org-anic solvent such as ether, benzene, ethyl acetate, or the like,with ether being preferred, the ether solution isdried'andconcentrated'according to conventional methods, Whereuponthe isolatedfree base, 5-benzyloxy-3-(2- a-minoe-thyl)-indole is reacted with adialkyl ketone in the presence of hydrogen and a platinum catalyst asoutlined above.

The following examples will serve to illustrate the process and productsof this invention, but the said invention is not to be considered aslimited thereto.

Example 1 .5-benzyl0xy-3- [2- (N-isopropylamirto ethyl] -indole andsalts thereof To 0.8 gram of 5-benZyloxy-3-(Z-aminoethyD-indolehydrochloride, dissolved in water, was added 25 milliliters of tenpercent sodium hydroxide solution and the liberated free base thereafterwas extracted with ether. The ether extract was dried with magnesiumsulfate, the ether distilled, the remaining oil dissolved in methanol,and the mixture added to 0.25 gram of pre-reduced Adams platinum oxidecatalyst. To the resulting mixture Was added 0.22 gram of acetone, themixture shaken with hydrogen at about two atmospheres pressure and at atemperature of about 25 degrees centigrade, and in about thirty minutesthe hydrogen consumption was complete. The catalyst was removed byfiltration, and the filtrate concentrated by distillation to yield thefree base. The free base, dissolved in ether, was reacted with gaseoushydrochloric acid to yield the 5benzyloxy- S-[Z-(N-isopropylamino)ethyl] indole hydrochloride which was filtered and recrystallized fromisopropanol. The yield of 5-benzyloxy-3-[2-(N-isopropylamino)-ethyl]indole hydrochloride, melting at 201-202 degrees centigrade, was 0.33gram (forty percent).

Anal-Percent calc. for C20H24N2QHC1: C, 69.66; H, 7.31. Found: C, 69.95;H, 7.34.

In essentially thesame manner as disclosed in Example 1, the following5-benzyloxy-3-EZ-(N-isopropylamino) ethyll-indoles and acid additionsalts thereof are prepared by reacting acetone with the corresponding 5-benzyloxy 3 (Z-aminoethyl) indole:5-(para,para'-dimethylbenzhydryloxy)-3-[2-(N-isopropylamino) ethyl]-indole, 5-(para,para-dichlorobenzhydryloxy) 3 [2-(N-isopropylamino)-ethyl]-indole, 5-(para,para-dimethoxybenzhydryloxy)-3-[2-(N-isopropylamino)-ethyl] indole, Z-methyl-S-benzyloxy 3[Z-(N-isopropylamino)-ethyl]- indole, or the like.

Example 2.-2-methyl-5-benzhydryl0xy-3-[2-(N-is0pr0- pylamin)-ethyl]-ind0le and salts thereof In essentially the same manner as given inExample 1, Z-methyl-S-benzhydryl-oxy 3 [2-(N-isopropylam-ino)-ethyll-indole is prepared by reactingZ-methyl-S-benzhydryloxy-3-(2-aminoethyl)-indo1e with acetone in thepresence of hydrogen and a platinum oxide catalyst and adding astoichiometric quantity of hydrogen chloride thereto to prepareZ-methyl-S-benzhydry1oxy-3-[2-(N-isopropylamino) -ethyl] -indolehydrochloride.

Example 3 -benzyl0xy-3 -[2-N -(4-heptylami:z0)-

ethyl] -ind0le and salts thereof In essentially the same manner as givenin Example 1, 5 -benzyloxy-3-E 2-N-(4'-heptylamino) ethyl] -indole isprepared by reacting 5-benzyloxy-3-(l aminoethyl)-indole with n-dipropylketone in the presence of hydrogen and a platinum oxide catalyst, andadding a stoichiometric quantity of picric acid thereto to prepare5-benzyloxy-3- [2-N-(4'-heptylam-ino)-ethyl] -indole picrate.

Example 4.-5-benzyloxy-3- [2-N-(3-amylamino)- ethyl] -ind0le and saltsthereof In essentially the same manner as given in Example 1,5-benzyloXy-3-[2-N-(3-amylamino)-ethyl]-indole is prepared by reacting5-benzyloxy-3-(Z-aminoethyl)-indole with n-diethyl ketone in thepresence of hydrogen and a platinum oxide catalyst and adding astoichiometric quantity of sulfuric acid thereto to prepare5-benzyloxy-3- [2-N(3-amylaminc)-ethyl] indole sulfate.

It is to be understood that this invention is not to be limited to'the'exact details of operation or exact compounds shown and described, asobvious modifications and equivalents will be apparent to one skilled inthe art, and the invention is therefore to be limited only by the scopeof the appended claims.

I claim:

1. In :a process for the preparation of (5-benzyloxy-3-indole)-alkylamines, the step of reduct-ively alkylating the aminoradical of a 5-benzyloxy-3-(Z-amiuoethyl)-indole with a (ii-(lower-alkyl)-ketone in the presence of hydrogen and a platinum catalyst.

2. In a process for the preparation of (5-benzyloxy-3-indole)-alkylamines, the step of reductively alkylating the aminoradical of a 5-benzyloxy-3-(Z-aminoethyl)-indole having the formula:

OHzCHzNH:

wherein X is selected from the group consisting of phenyl, halophenyl,lower alkoxyphenyl, and lower .alkylphenyl, Y is selected from the groupconsisting of hydrogen, pheny-l, halophenyl, lower alkoxyphenyl, andlower alkylphenyl, and R is selected from the group consisting ofhydrogen and lower alkyl with a di-(lower alkyD-ketone in the presenceof hydrogen and a platinum catalyst.

3. In a process for the preparation of a S-benzyloxy-3-EZ-(Ndsop-ropyl-amino)-ethyl]-indole, the step of reductivelyalkylating the amino radical of a 5-benZyloxy-3-(2- aminoethyl)-indolewith acetone in the presence of hydrogen and a platinum catalyst.

4. In a process for the preparation of a 5-benzyloxy-3-[2-(N-isopropylamino)-ethyl]-indole, the step of reductivelyalltylating the amino radical of a 5-benZyloxy-3- (2-a-minoethyl)-indolehaving the formula:

wherein X is selected from the group consisting of phenyl, halophenyl,lower alkoxyphenyl, and lower alkylphenyl, Y is selected from the groupconsisting of hydrogen, phenyl, halophenyl, lower alkoxyphenyl, andlower alkylphenyl, and R is selected from the group consisting ofhydrogen and lower alkyl with acetone in the presence of hydrogen and aplatinum catalyst.

5. In a process for the preparation of 5-benzyloxy-3-[2-(N-isopropylamino)-ethyll-indole, the step of reductively alkylatingthe amino radical of 5-benzyloxy-3-(2- aminoethyl)-indole with acetonein the presence of hydrogen and a platinum catalyst.

6. A compound selected from the group consisting of (l) a(S-benzyloxy-S-indolyl)-alkylamine having the formula:

H lower-alkyl wherein X is selected from the group consisting of phenyl,halophenyl, lower alkoxyphenyl, and loweralkylphenyl, Y is selected fromthe group consisting of hydrogen, phenyl, halophenyl, loweralkoxyphcnyl, and lower alkylphenyl, and R ,is selected from the groupconsisting of hydrogen and lower alkyl and (2) acid addition saltsthereof.

7. 5 benzyloxy 3 -f'[2 (N isopropylamino) ethyl]- indole hydrochloride.

6 OTHER REFERENCES 5 8. 5 benzyloxy 3 [2 (N isopropylamino) ethyl]-indole- Adams et 211.: Organic Reactions v01. 4 182-183.

2 {methyl 5 benzhydryloxv [2 (N J. Chem. Soc. (London) p. 1726 1937Propyrdlnlno)'efllyl]111C101e hydrochlonde- The Chemistry ofHeterocyclic Compounds (Indole 5 and Carbazole), Sumpter et aL,Interscience Pub. Inc.,

10. 5 benzyIoxy-3-[2 N (4' heptylamino ethyl]- indole picrate. N Y 19541 9-200 11. 5 benzyloxy 3 [2 N (3' amylamino)- 9 ethyl] -indole sulfate.

References Cited in the file of this patent UNITED STATES PATENTS Klareret al Feb. 17, 1931 Jenkins et al Feb. 18, 1947

1. IN A PROCESS FOR THE PREPARATION OF(5-BENZYLOXY-3INDOLE)-ALKYLAMINES, THE STEP OF REDUCTIVELY ALKYLATINGTHE AMINO RADICAL OF A 5-BENZYLOXY-3-(2-AMINOETHYL)-INDOLE WITH ADI-(LOWER ALKYL)-KETONE IN THE PRESENCE OF HYDROGEN AND A PLATINUMCATALYST.